Dioscin induces M1 macrophage polarization through Connexin-43 Channels in Tumor-associated-macrophages-mediated melanoma metastasis

Yu Kou; Qidi Sun; Rentao Zhu; Zhijie Lin; Zhuoqun Li; Hairong Xu; Xuan Feng; Yanqing Liu

doi:10.1016/j.phymed.2022.154559

Dioscin induces M1 macrophage polarization through Connexin-43 Channels in Tumor-associated-macrophages-mediated melanoma metastasis

Phytomedicine. 2023 Jan:109:154559. doi: 10.1016/j.phymed.2022.154559. Epub 2022 Nov 21.

Authors

Yu Kou¹, Qidi Sun², Rentao Zhu², Zhijie Lin³, Zhuoqun Li², Hairong Xu², Xuan Feng⁴, Yanqing Liu⁵

Affiliations

¹ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu, China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225000, Jiangsu, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou 225000, Jiangsu, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225000, Jiangsu, China. Electronic address: kouyu@yzu.edu.cn.
² Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu, China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225000, Jiangsu, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou 225000, Jiangsu, China.
³ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu, China.
⁴ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu, China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225000, Jiangsu, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou 225000, Jiangsu, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225000, Jiangsu, China.
⁵ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu, China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225000, Jiangsu, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou 225000, Jiangsu, China. Electronic address: liuyq@yzu.edu.cn.

PMID: 36610151
DOI: 10.1016/j.phymed.2022.154559

Abstract

Background: Tumor-associated macrophages (TAMs) are important constituent parts of tumor microenvironment that connected with tumor metastasis in melanoma. Connexin 43 (Cx43) was expressed in all the immune cells which modulated different aspects of immune response. However, the concrete molecular mechanism maintains unclear.

Purpose: The study aimed to find a natural drug monomer effectively reversed the polarity of tumor-associated macrophages inhibiting melanoma metastasis and improving survival time.

Methods: Flow cytometry was used to determine the effects of dioscin on the macrophage phenotype. Western bolt and ELISA were performed to explore the underlying mechanism of dioscin and a co-culture experiment in vitro was applied to assess the role of dioscin on TAMs-mediated melanoma proliferation, invasion and migration. Moreover, in vivo melanoma metastasis models were established for examining effects of dioscin on TAMs-mediated melanoma metastasis.

Results: Dioscin repolarized macrophages from M2 towards M1-like phenotype. Dioscin suppressed M2-like phenotype macrophages through enhanced the expression and transport function of Cx43. Furthermore, the stimulation IFN-γ/STAT1 pathway and suppression IL-4/JAK2/STAT3 pathway were major mechanism of dioscin. Importantly, dioscin suppressed Cx43^G21R mutation TAMs induced proliferation, invasion, migration and metastasis of melanoma cells. It worthily noting that dioscin ameliorated tumor-associated-macrophages-mediated melanoma metastasis in vitro and vivo.

Conclusion: Dioscin re-polarized macrophages from M2 to M1 phenotype through activation of Cx43-gap-junction-intercellular-communications (Cx43-GJs)/IFN-γ/STAT1 pathway and inhibition of Cx43-GJs/IL-4/JAK2/STAT3 suppressing migration, invasion and metastasis of melanoma, which provided a theoretical and experimental basis for treating melanoma metastasis.

Keywords: Connexin 43; Dioscin; Invasion and metastasis; Melanoma; Tumor-associated macrophages.

MeSH terms

Cell Line, Tumor
Connexin 43* / metabolism
Humans
Interleukin-4 / metabolism
Macrophages
Melanoma* / pathology
Tumor Microenvironment
Tumor-Associated Macrophages / metabolism

Substances

Connexin 43
dioscin
Interleukin-4